Mycobacterium tuberculosis (MTB) is readily transmitted by inhalation of aerosolized mycobacteria. As T cell immunity develops, growth of MTB is controlled. Despite robust activation of innate and adaptive immunity, however, MTB resists and evades these responses to survive and persist. MTB blocks the effects of oxygen radicals, modulates the phagosome in the macrophage to its advantage by inhibiting acidification and fusion with lysosomes. CD4+ T cells are central to adaptive immunity to MTB and MTB modulates CD4+ T cell responses. First, prolonged TLR-2 stimulation by mycobacterial lipoproteins inhibits MHC-II antigen processing by macrophages for CD4+ T cells. Second, MTB phosphotidyl-inositol mannoside (PIM) interacts with VLA-5 (Valpha5beta1) on CD4+ T cells and induces adhesion to fibronectin. Third, the MTB cell wall contains additional molecule(s) that affect IFN-gamma signaling and CD4+ T cell co-stimulation. Thus the interaction between MTB and T cells is determined by the balance between the host's ability to optimally activate T cells, and MTB's ability to inhibit or deviate T cell recognition and effector function. This model generates the following testable hypotheses: First, MTB uses multiple molecular mechanisms to directly and indirectly (i.e. through the ARC) modulate CD4+ T cell responses to mycobacterial proteins. Second, MTB uses distinct host receptors (e.g. TLR-2, IFN-gammaR, VLA-5) to modulate these T cell responses. Third, differential sensitivity to MTB mediated modulation of ARC and T cell function allows T cell subsets to complement each other. The aims to test these hypotheses are: 1. To determine the cellular events associated with VLA-5 dependent PIM-induced human CD4+ T cell migration and adhesion to fibronectin (FN), and to compare different PIM families and species in their ability to induce CD4+ T cell adhesion and migration;2. To determine the identity and mechanism of a novel MTB molecule that co-stimulates human memory CD4+ T cells in the presence of extracellular matrix protein, FN;3.To determine if human T cell subsets ( CD4, CDS, gammadelta Tregs) differ in sensitivity to molecules MTB, such as PIM and the co-stimulator of Aim 2, that modulate memory CD4+ T cells. These studies will provide insight into how MTB can regulate T cell responses to mycobacterial antigens.